Fig. 7: Mechanism for Semaphorin 5A action on abnormal activation of RA SFs. | Cell Death & Disease

Fig. 7: Mechanism for Semaphorin 5A action on abnormal activation of RA SFs.

From: Semaphorin 5A suppresses ferroptosis through activation of PI3K-AKT-mTOR signaling in rheumatoid arthritis

Fig. 7: Mechanism for Semaphorin 5A action on abnormal activation of RA SFs.The alternative text for this image may have been generated using AI.

SMs secrete a large amount of Semaphorin 5A, leading to an increased level of Semaphorin 5A in the synovial fluid. Semaphorin 5A then binds to Plexin-A1 and Plexin-B3 on SFs and activates the PI3K/AKT/mTOR signaling pathway. Activated mTORC1 signaling inhibits lipid peroxidation, ROS production, and ferroptosis by increasing the phosphorylation of 4E-BP1, leading to increased protein synthesis of GPX4, and also by activating downstream SREBP1/SCD-1 signaling. Reduced ferroptosis leads to increased survival of SFs, further promoting inflammation and immunity. SFs synovial fibroblasts, SM synovial macrophages.

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